POSTTRANSCRIPTIONAL REGULATION OF TRANSFORMING GROWTH FACTOR-BETA 1

在许多细胞类型中，测量到的 转化生长因子-β1的mRNA和蛋白水平。此外，转化生长因子-β1通常是 以生物逻辑潜伏的形式分泌，必须在 结合到细胞表面。这表明翻译或后翻译- 翻译机制在转化生长因子-β的调节中起重要作用 Beta1制作。类固醇激素中临床上重要的成员 超级家族影响着这两个过程。要调查翻译 调节、表达构建体已经制成，其中各个部分 在转化生长因子-β1基因的5‘和3’非翻译区中 已被删除。MRNAs的内在可译性由以下因素决定 体外翻译，而体内翻译的效率相同 稳定转染的乳腺癌细胞系中的构建物给出了 涉及任何交易因素的信息。结果是 复杂但表明(I)翻译效率取决于以下哪一项 使用替代的转录起始点，(Ii)3‘-UTR 刺激翻译，以及(Iii)3‘和5’-UTRs组合具有非 相加效应，暗示了信使核糖核酸两端之间的串扰。 已建立了准确测量转化生长因子-β的方法学。 受试者的血浆。正常对照组显示出显著水平的 血浆循环中的转化生长因子-β1(2.5+/-1.4 ng/ml；n=37)。这 提示了迄今为止未被怀疑的转化生长因子-β的内分泌作用。流通中 转化生长因子-β是一种生物潜伏形式，与 α-2-巨球蛋白。对机制的理解，从而 类固醇和相关化合物调节细胞的产生和活动 转化生长因子-β家族的生长抑制物可能允许合理设计更多 用于化学预防或化疗的强效药理制剂 癌症的威胁。

In many cell types there is a large discrepancy between the measured levels of TGF-beta1 mRNA and protein. Furthermore, TGF-beta1 is generally secreted in a bio-logically latent form that must be activated prior to binding to the cell surface. This suggests that translational or post- translational mechanisms play an important role in the regulation of TGF- beta1 production. Clinically important members of the steroid hormone superfamily affect both these processes. To investigate translational regulation, expression constructs have been made in which various portions of the 5' and 3' untranslated regions (UTRs) of the TGF-beta1 cDNA have been deleted. The intrinsic translatability of the mRNAs is determined by in vitro translation, while in vivo translation efficiency of the same constructs in stably transfected breast cancer cell lines gives information on involvement of any transacting factors. Results are complex but indicate that (i) translational efficiency depends on which of the alternate transcriptional start sites are employed, (ii) the 3'-UTR stimulates translation, and (iii) the 3' and 5'-UTRs combined have non- additive effects, suggesting cross-talk between the two ends of the mRNA. Methodology has been developed for accurate measurement of TGF-betas in the plasma of human subjects. Normal controls show significant levels of circulating TGF-beta1 in the plasma (2.5 +/- 1.4 ng/ml; n=37). This suggests a hitherto unsuspected endocrine role for TGF-beta. Circulating TGF-beta is in the biologically latent form and is not associated with alpha-2-macroglobulin. An understanding of the mechanisms whereby steroids and related compounds regulate the production and activity of the TGF-beta family of growth inhibitors may allow the rational design of more potent pharmacological agents for use in chemoprevention or chemotherapy of cancer.